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Testosterone is considered to be the primary male androgen. It is responsible for the development and maintenance of male sexual characteristics, including external virilization, sexual maturity at puberty, spermatogenesis, sexual behavior/libido and erectile functioning. It also supports bone and muscle tissue growth, and remains vital to ones health and well being throughout life. After physical maturity, men often notice a slow decline in the level of testosterone produced by the body. Dubbed andropause, subnormal androgen levels can lead to a decline in muscle mass, libido, sexual functioning and overall sense of well being later in life. In many instances this indicates a need for some form of androgen replacement.
A number of methods have been developed to restore androgen concentration in humans with declining levels. Several injectable esterified testosterone preparations have been fashioned that allow a slow release of hormone into the blood stream over the course of several days to weeks for example, however all provide inconsistent dosing as there is great variance in hormone release from the site of injection, such that a short supraphysiological rush may eventually be followed by days of subnormal hormone concentrations. The buildup of estrogens due to the natural process of aromatization may exaggerate the side effects to such medication, particularly at times when testosterone levels are abnormally high, as supraphysiological levels of estrogens in the male body have been linked to gynecomastia (female breast tissue development), water retention and edema, and increased fat deposition.
Also a number of synthetic oral androgen derivatives have been developed including methyltestosterone, fluoxymesterone and stanozolol. All such compounds are alkylated at the 17th carbon position (alpha orientation), an alteration that inhibits reduction of the steroid to inactive 17-ketosteroid form. While this greatly improves oral bioavailability of the compound, this alteration has also been shown to place stress on the liver, in some instances resulting in organ damage. Although the use of a c-17 alpha alkylated oral androgen may prove much more comfortable for the patient in terms of dosing and control over blood hormone level compared to an injectable preparation, the possible risk of developing complications with liver functions may make them much less useful for androgen replacement compared to injectable preparations, particularly for extended periods of therapy.
In searching for a less toxic, more reliable oral alternative for androgen replacement the use of androgen precursor hormones have been suggested. U.S. Pat. No. 5,880,117 to Patrick Arnold relates a method of using the precursor hormone 4-androstene-3,17beta-diol as a means of increasing testosterone levels in humans. The pharmacokinetics of administering such a precursor are such that hormone concentrations of active hormone (testosterone) peak within 90 minutes, and subsequently decline over a period of three to four hours. This more closely resembles the natural pulsating pattern in which the body releases testosterone, and avoids the prolonged peaks and troughs noted with use of esterified injectable hormone preparations. Although the precursor hormone 4-androstene-3,17beta-diol discussed in this patent has been shown to effectively convert to testosterone after administration and represents a great improvement over previous androgen replacement methods, it is also not the most ideal isomer of this hormone to use for this purpose. U.S. Pat. No. 5,880,117 to Patrick Arnold specifically excludes the 3-alpha isomer 4-androstene-3alpha, 17beta-diol in its scope, which according to this invention is a much more active precursor to the testosterone molecule than the 3-beta.
U.S. Pat. No. 5,880,117 relates a novel method of using a direct precursor hormone to testosterone as a means of replacing androgen levels in men. Although the suggested practice of using a precursor to the active steroid testosterone seems quite sound, the precursor in this patent (4-androstene-3,17beta-diol) is not extremely active at converting to testosterone in the human body. The problem of the present invention is therefore to provide another precursor to testosterone that can be used to replace androgen action in humans, but with a much greater level of efficacy. According to the invention this problem is solved by the use of 4-androstene-3alpha, 17beta-diol. The mentioned androgen precursor hormone is ideal because it demonstrates a much more complete level of conversion to testosterone in human.
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